Structure-activity relationships of acyclic nicotinoids and neonicotinoids for insect nicotinic acetylcholine receptor/ion channel complex

The insect nicotinic acetylcholine (ACh) receptor (nAChR) is a target site for the neonicotinoid insecticides such as imidacloprid and its acyclic derivative acetamiprid. The structure-activity relationships of acetamiprid homologues and 3-pyridylmethylamines (known as the essential structural requirement of nicotinoid) are compared in terms of the affinity to the [H-3]alpha- bungarotoxin (alpha-BGT) site (designated as ACh site) and the [H-3]phencyclidine (PCP) site [designated as noncompetitive blocker (NCB) site] of the insect nAChR from the honeybee heads. Increasing the chain length of alkyl substituents (from methyl to n-butyl) on an amino nitrogen atom of acetamiprid homologue and 3-pyridylmethylamine reduces the potency as inhibitors of [H-3]alpha-BGT binding, whereas it confers the enhanced potency as inhibitors of [H-3]PCP binding in the insect nAChR. Scatchard analysis reveals that homologues of acetamiprid and 3-pyridylmethylamine having n-butyl substituents interact with the high-affinity binding site for [H-3]PCP, which is considered to be the NCB site located in the ion channel of the insect nAChR. The interaction of acetamiprid homologues with the ACh or NCB site of nAChR is selective for insects, while that of the 3-pyridylmethylamines is effective for both insect and Torpedo [Tomizawa et al., J Pesticide Sci 21:412-418 (1996)], The explorations in further structural modification of neonicotinoid compounds may facilitate development of new insecticides or probes for the ion channel of insect nAChR. (C) 1998 Wiley-Liss, Inc.